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Pathology > Genetic Diseases > Flashcards

Genetic Diseases Flashcards

1
Q

Chromosomal disorders

A
  • Aneuploidy- abnormal chromosome number, non-dijunction in meiosis
  • Trisomy
  • Monosomy
  • Polyploidy (multiple sets)
  • Structural abnormalities
  • rearrangement
  • deletion
  • translocation
  • inversion
  • duplication
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2
Q

Clinical indication of chromosome analysis

A
  • Problems of early growth and development
  • Stillbirth and neonatal death- history of miscarriages
  • Fertility problems
  • Family history
  • Neoplasia
  • Pregnancy in a woman of advanced age, or with an increased risk screening result
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3
Q

Down syndrome

A
  • Major cause of intellectual disability ad congenital heart disease
  • characteristic facial and physical features
  • congenital abnormalities of GIT, increased risk of leukaemia, immune system defects, and an Alzheimer-like dementia (premature aging)
  • 95% of cases due to trisomy 21
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4
Q

FISH

A

Fluorescence In Situ hybridization

-Fluorescently tag chromosome of interest

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5
Q

Rearrangement and Down syndrome

A
  • Recipricol translocation between chr 21 and 14
  • Unbalanced, the 14 has some 21 on it
  • Parent passes on chr 21, and a 14 with some 21 on it, child has too much chr 21 material
  • Trisomic for 21
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6
Q

Microarray, DNA chip

A
  • DNA sequences and/or gene expression

- look at SNPs, or larger changes eg number of chromosomes, or copy number variation (CNVs)

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7
Q

Molecular karyotyping

A
  • Comparative genome hybridization molecular karyotyping
  • Probe along entire genome
  • Variable resolution
  • Look for deletions, microdeletions etc
  • Does not detect point mutations, small deletions/duplications or triplet repeats
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8
Q

Single gene disorders

A
  • Genotype phenotype correlation
  • Remember can be mitochondrial
  • Penetrance, variable expressivity, genetic heterogeneity etc
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9
Q

Direct genetic testing

A
  • PCR
  • RFLPs- restriction fragment polymorphisms
  • Microarrays
  • Sequencing
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10
Q

Beta Thalassaemia

A
  • Mutation causing decreased synthess of one or more beta globulin chains in haemoglobin
  • Imbalance in alpha and beta chains- homotetramer 9al alpha globulin)
  • Homotetramers precipitate in RBCs and lead to their destruction and subsequent anaemia
  • Point mutation at restriction enzyme cutting site (NcoI)
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11
Q

Polygenic/multifactorial disorders

A
  • Additive contribution of several genes
  • Input f genes not always equal, often only a small input
  • Test using genome wide association studies (GWAS)
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12
Q

What is genetic testing done for?

A
  • Clinical diagnosis- symptoms present
  • Carrier testing
  • Predictive testing (HD and BRAC1/2)
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13
Q

Prenatal diagnosis

A
  • Risk information
  • Help prepare parents and doctors for arrival of baby
  • Chorionic villus sampling or amniocentesis
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14
Q

Chorionic villus sampling

A
  • From 11 weeks gestation
  • Placental tissue
  • Ultrasound
  • Invasive, 1% increased risk of miscarriage
  • For termination- aspiration, general anaesthetic
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15
Q

Amniocentesis

A
  • 15-16 weeks gestation
  • Amniotic fluid with sloughed fetal cells
  • Ultrasound
  • Invasive, 0.5% increased risk of miscarriage
  • For termination, induced labour
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16
Q

Pre-implanation genetic diagnosis (PGD

A
  • From zygote at 8 or 10 cell stage
  • IVF
  • Unaffected embryos implanted
17
Q

Cell free foetal DNA/RNA in maternal blood- non invasive

A
  • Introduced in clinical settings in Aus 2013, from 10 weeks gestation
  • Next generation sequencing
18
Q

Genetic screening

A
  • Identifies a subset of individuals at high risk of having, or transmitting to children, a specific genetic disorder
  • eg ethnicity
  • Often not definitive- changing with advances in gene technology
  • False positive and false negatives
  • Prevent disease, early treatment, future reproductive options, decrease social and financial burdens
19
Q

Criteria of screening for a genetic condition

A
  • Must be an important health problem, severe and/or common
  • Must be preventable or treatable by acceptable means (includes prenatal)
  • Screening test must be simple, safe, reliable and acceptable, relatively inexpensive
  • Education and conselling facilities must be generally available- informed decision making
20
Q

Population genetic screening in VIctoria

A
  • Prenatal screening
  • Foetus: chromosomal +/- neural tube defects
  • Parents: carrier status for haemoglobinopathies and cystic fibrosis (CF) in high risk ethnic groups
  • Newborn screening (eg PKU)
  • Pre-conception carrier screening
21
Q

Prenatal screening

A
  • Offered to all pregnant women
  • Ultrasound/nuchal translucency (oedema)
  • Maternal serum screening, biomarkers, 1st and 2nd trimester
  • NIPT screening
  • Without testing foetal cells
  • Screening tests not always genetic- look for biochemical markers
22
Q

Muscular dystrophies

A
  • Group of inherited disorders of muscle
  • Muscle histology has distinctive feaetures- muscle fibre necrosis, phagocytosis etc
  • No clinical or laboratory evidence of central or preipheral nrervous system involvement or myotonia
  • Numerous different types, duchennes most severe and common
23
Q

Symptoms of DMD

A
  • Floppy muscles (hypotonia)- sometimes
  • Often a delay in walking, toe walking
  • Clumsy, falling over, inability to run properly (waddle)
  • Gowers sign (climbing up legs from lying position)
  • Muscle pseudohypertrophy (excess fat and connective tissue
  • Lumbar lordosis (sway back) and protuberant abdomen
  • IQ
  • Deletion affecting reading frame, or mutation- premature termination, non-functional protein produced
24
Q

Cause of symptoms

A
  • Increasing proximal limb muscle weakness due to progressive muscle degeneration
  • Caused by mutation(s) in a gene encoding a muscle protein called dystrophin
  • Dystrophin is found in all muscle (sub sarcolemma) and brain
  • Forms link between actin (cytoskeletal) and ECM
25
Q

Effect sof dystrophin deficiency

A

Abscence of/altered dystrophin leads to membrane instability.
This results in an increased Ca2+ influx and increase in proteollytic and lipolytic activity. The muscle has a process of degradation and regeneration, where the degradation outweighs the regeneration

26
Q

Outcomes of DMD

A
  • Scoliosis, may require surgical insertion of a metal rod
  • Wheelchaor usually by age 12
  • Respiartory or cardiac failure
  • Death in late teens, increasingly survive until 30’s
27
Q

Treatments for DMD

A
  • Medical (primarily corticosteroids)

- Occupational and physiotherapy to improve outcome

28
Q

Becker BMD

A
  • Milder than DMD
  • May never have a wheelchair, if they do, not before 16
  • Fertility reduced, not abolished
  • Mutation doesn’t affect reading frame- shorter and only partially functional protein
29
Q

Inheritance of DMD and BMD

A
  • X-linked recessive
  • Duchenne’s more prevalent
  • In 2/3rds of isolated (no known family history) the mother is a carrier
  • Up to half of carriers show mild symptoms
  • 1/3rd cases de novo
30
Q

Diagnosis

A
  • Creatine kinase in blood to screen, the muscle isoform is elevated 20-50x
  • Pathology of muscle biopsy (gold standard, but invasive and not nice), abnormal variation in diameter (hypertrophy and atrophy), central nuclei, focal necrotic and regenerative fibres, foci of inflammatory cells, extensive replacement of muscle fibres with fat and fibrous tissue, immunocytochemistry
  • DNA tests- direct testing for deleting, sequencing. Indirect testing- linkage, look at genes also on that chromosome- compare to mums chrom and make sure sibling didn’t get the chromosome most likely to have the disease
31
Q

Multiplex ligation-dependent probe amplification- MLPA

A
  • PCR-based
  • Can quantitatively detect deletions or duplications in all 79 exons of dystophin gene
  • Able to detect carriers of deletions- DMD and BMD
  • Probes designed that they’re only detected if they can hybridise to corresponding exon
  • Does not detect the 1/3rd of cases caused by point mutations
  • Microdeletions or point mutations around ligation site are reported as deletions
32
Q

Linkage analysis

A
  • Linkage analysis is done when deletions are not found in the boy, so we wish to determine the disease causing chromosome (which of mums two X chromosomes have the point mutation). Used for carrier testing or prenatal diagnosis
  • Track the mutated gene using tandem repeats or introns- but crossing over during meiosis can skew results
33
Q

Carrier testing

A
  • Knowing carrier status informs reproductive risk for future children
  • If a mutant is not detected in affected boy by MLPA, then we can calculate carrier status the final likelihood of being a carrier by combining
  • pedigree, linkage, creatinine kinase
34
Q

Future therapy possibilities

A
  • Currently no cure for DMD- clinical trials
  • Gene therapy- may ned to use a modified “mini-gene” because the dystrophin gene is so large
  • Up-regulation of alternative proteins eg utrophin (a dystrophin homologue, high levels in foetal tissue)
  • Anti-sense oligonucleotides that allow skipping of exons to produce shorter, partially functional protein, as opposed to an early stop signal
  • Drugs to restore dystrophin production in those due to stop/nonsense mutation (allow “read through”
  • Drugs to inhibit protein degradation or increase muscle mass, strength, or function
  • Myoblast transfer therapy-myoblasts containing normal dystrophin gene are implanted
  • Stem cell therapy

Pathology (23 decks)

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